Viral Infections and Childhood Asthma

JAN L. L. KIMPEN

Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands

	INTRODUCTION

TOP INTRODUCTION WHEEZING-ASSOCIATED RESPIRATORY... ACUTE VIRUS-INDUCED ASTHMA... POSTBRONCHIOLITIS WHEEZING VIRAL INFECTIONS PREDISPOSING... CONCLUSION DISCUSSION REFERENCES

Formulating hypotheses on the pathogenetic links between viral infection in childhood and asthma requires an undisputed definition of asthma. Unfortunately, many wheezing syndromes have been recognized in the pediatric age group, which are the subject of a vivid controversy on the exact terminology. Leaving a detailed definition of childhood asthma aside, at least four different wheezing syndrome have been associated with viral infections: (1) wheezing-associated respiratory infections in infancy and early childhood, (2) asthma attacks associated with or elicited by viral upper respiratory tract infections in older children, (3) recurrent wheezing episodes after viral bronchiolitis, and (4) atopic asthma. There is no doubt that some overlap exists between these various wheezing syndromes. Epidemiological observations have stimulated the study of possible pathogenetic mechanisms underlying the relation between viral respiratory tract infections and these wheezing syndromes.

	WHEEZING-ASSOCIATED RESPIRATORY INFECTION

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Although the term wheezing-associated respiratory infection (WARI) has disappeared gradually from the literature, it is used in this overview to describe a wheezing syndrome in children younger than 5-6 yr of age, who have signs and symptoms of airway obstruction during viral infections of the upper and lower respiratory tract. They do not feature a tendency toward a family history for atopy, nor do they have positive skin tests or a high level of serum IgE. These children outgrow their symptoms by the age of 5 to 6 yr and have been termed early wheezers (1). The viruses involved are respiratory syncytial virus (RSV), influenza and parainfluenza viruses, adenovirus, and possibly rhinovirus (2). The pathogenesis of this syndrome is not well understood. A small caliber of the airways associated with unusual lung mechanics might be the most important determining factor responsible for recurrent or protracted bronchus obstruction in this age group, even after trivial respiratory insults, such as mild viral infections (3). There might also be a genetically determined premorbid abnormal lung function. In the absence of protective immunological memory, mild viral infections might induce more or less severe inflammation of the airways during initial viral infections, possibly accompanied by prolonged periods of hyperreactivity (3). Finally, maternal smoking during pregnancy can also play a role (4). It is plausible that mechanisms other than those active in atopic asthma are playing an important role in children with WARI episodes, because these patients respond only marginally to bronchodilators and corticosteroids, drugs that are effective in the acute and long-term treatment of atopic asthma in the older child.

	ACUTE VIRUS-INDUCED ASTHMA EPISODES

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It has been shown that more than 80% of asthma attacks in children are accompanied by a viral upper respiratory tract infection, or at least the isolation of a respiratory virus from the upper respiratory tract (5). Rhinovirus is probably the most important pathogen in this regard, although other viruses might play a more important role in other geographic areas. Probably any virus that is capable of producing an acute respiratory infection is capable of producing an asthma exacerbation (2). This illustrates the difficulty and possibly the inappropriateness of differentiating between wheezing-associated respiratory illness in children less than 5 yr old and virus-associated asthma attacks in older children.

The immunopathogenic mechanisms involved in the intricate relation between viral infections and bronchus obstruction in individuals with asthma have received considerable attention. Natural or experimental viral infection of respiratory epithelial cells induces activation of transcription factors such as the RelA subunit of NF-B and NF-IL-6, thus initiating the gene transcription leading to production and release of cytokines and chemokines in vitro and in vivo (IL-8 [interleukin 8], RANTES [regulation on activation, normal T cell expressed and secreted], IL-11, IL-6, IL-1, MCP-1 [membrane cofactor protein 1], and macrophage inflammatory protein 1 [MIP-1]) (6). These mediators promote cellular infiltration by T cells, eosinophils, and basophils. These cells become activated and can release inflammatory mediators such as eosinophil cationic protein (ECP) and histamine as well as possibly virus-specific IgE. This cascade probably results in airway inflammation and bronchial hyperresponsiveness with a decreased PC₂₀ (provocative concentration of agonist causing a 20% fall in FEV₁), leading to more or less protracted airway obstruction. Although these inflammatory phenomena can be induced in both subjects with atopic asthma and normal control subjects, the persistence and severity of the eosinophilic inflammation seem to be more pronounced in the former group, possibly through an immunological imbalance in helper T cell type 1 (Th1)- and Th2-type cytokines produced by the cellular infiltrate. That this imbalance in the Th1/Th2 dichotomy does not function as an on-off mechanism is illustrated by the observation that in an RSV-mouse model eosinophilic infiltration of the airways (a Th2 phenomenon) can be seen in the abundance of interferon  (IFN-), a typical Th1 cytokine (12).

	POSTBRONCHIOLITIS WHEEZING

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Epidemiologic studies have demonstrated that 40-50% of patients with RSV bronchiolitis develop recurrent episodes of wheezing in early childhood, together with persistent bronchial hyperresponsiveness and lung function abnormalities (13). It is still controversial whether atopy adds to this increased risk for recurrent wheezing or not.

Several possible mechanisms have been proposed to explain this epidemiological association. First, immaturity of the immune system at the time of the initial infection and the clinical syndrome of bronchiolitis might cause slower recovery of the airway hyperresponsiveness and increased vulnerability to nonspecific stimuli or subsequent mild viral infections in the years following the initial episode. No clear epidemiologic or pathogenic data except the fact that RSV disease is more severe in younger infants underscores this statement. However, observations in our laboratory show a less pronounced lymphocyte activation in younger children, possibly causing a less complete recovery with more long-term complications in the younger age group (16).

Second, a different genetic background could make some patients more prone to both severe RSV infection and subsequent wheezing (17). The same genes that have been implicated in the genetics of asthma are candidates for this hypothetical genetic predisposition (18).

Third, it cannot be excluded that virus strain variability could be the cause for a different outcome. However, a review of the literature has not substantiated the claim that strain variability is responsible for disease severity (19). It has not been studied whether viral subgroups correlated differently with later recurrent wheezing.

Finally, an inappropriate immune response during the initial infection with RSV could be responsible for a more severe expression of disease (bronchiolitis versus upper respiratory infection) and the presence or absence of subsequent wheezing episodes (20). Figure 1 illustrates the normal or desirable immune cascade on infection with RSV. The virus infects epithelial cells, which are recognized by MHC class I-restricted CD8-positive lymphocytes resulting in virus-specific cytotoxicity. In the meantime viral proteins are processed and presented by antigen-presenting cells (e.g., alveolar macrophages) to MHC class II-restricted CD4-positive T cells resulting in the production and release of Th1 cytokines, followed by virus-specific IgG production and a beneficial memory response on subsequent infections. In addition, IFN- produced by RSV-specific CD8-positive T cells inhibits the initiation of a Th2 direction in the production of cytokines.

View larger version (17K): [in this window] [in a new window]   Figure 1.   Schematic illustration of the normal or desirable immune cascade on infection with RSV.

In all these steps disturbances might occur, with the final result being a Th2 cytokine profile with eosinophil and basophil activation and RSV-specific IgE production, along with the production of IgG and RSV-specific cytotoxicity (Figure 2). These changes in the immune response are not well understood. Data in the literature are conflicting. However, some consensus takes hold that live virus induces a Th1 cytokine profile in most individuals during an acute infection. On the other hand, individually expressed RSV proteins induce Th1 (F protein) or Th2 cytokines (G, N, and P proteins) (21). Although this information is of paramount importance for the development of an effective subunit vaccine, it is not clear how the various proteins influence the immune response in vivo during natural or experimental infection. To complicate the matter even more, it has been shown that the source of the cytokines (CD4- versus CD8-positive cells, or memory versus effector T cells) plays an important role in the final pathologic result in the airways (22, 23).

View larger version (22K): [in this window] [in a new window]   Figure 2.   Schematic illustration of disturbances that result in a Th2 cytokine profile with eosinophil and basophil activation and RSV-specific IgE production, along with the production of IgG and RSV-specific cytotoxicity.

	VIRAL INFECTIONS PREDISPOSING TO ATOPY

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There are two conflicting lines of evidence regarding the relationship between (viral) infections and the development of atopy or at least sensitization to nonviral antigens.

On the one hand, epidemiological studies have demonstrated that an increased incidence of infections in early childhood protects against the development of atopy and allergic symptoms. Nonwheezing lower respiratory tract infections in early life are associated with persistently diminished IgE levels (24). Children with more siblings have less skin-prick test reactivity (25). More intensive use of day-care centers (with an increased incidence of infectious diseases) correlates inversely with the prevalence of allergic symptoms. Finally, a striking difference in allergic diseases has been shown between the former East and West Germany, with less allergy (and more infections) in East Germany in comparison with the western side of the country (26). And finally, a strong Th1 response in the form of delayed-type hypersensitivity to Mycobacterium tuberculosis was associated with relative protection against the development of atopy and allergic symptoms (27).

On the other hand, experiments in laboratory animals suggest that sensitization to nonviral antigens can be induced by viral infection (28). In addition, RSV bronchiolitis appears to be a risk factor for sensitization to common aeroallergens in children with a positive family history for atopy and asthma (29). It is not clear whether the same is true for individuals without a positive family history.

	CONCLUSION

TOP INTRODUCTION WHEEZING-ASSOCIATED RESPIRATORY... ACUTE VIRUS-INDUCED ASTHMA... POSTBRONCHIOLITIS WHEEZING VIRAL INFECTIONS PREDISPOSING... CONCLUSION DISCUSSION REFERENCES

Asthma and respiratory virus infections are linked in an intricate way. Although epidemiological data are strong, the immunopathogenetic mechanisms involved are still incompletely understood. New insights into these mechanisms not only serve to enhance understanding of the pathogenesis of viral airway disease, but might eventually in the distant future lead to immunotherapy of asthma by means of strong Th1-stimulating vaccines, possibly in conjunction with Th2-inhibiting substances such as antiinflammatory cytokines.

	DISCUSSION

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Vercelli: What is the receptor for RSV?

Kimpen: For several viruses, among them rhinovirus, coronavirus, and EBV, the receptors are known, but not for RSV.

Kips: If I understand it well, viruses themselves can induce IL-11 production in a number of tissue structures, such as epithelial cells and fibroblasts; still it is not a Th1/Th2-specific cytokine. Very nice work by Dr. Elias' group has shown that if you selectively overexpress IL-11 in the airways of mice, you get pathological changes and you get an increase in airway responsiveness. Could it be, as an alternative hypothesis, that structural changes in the airways after RSV infection are due to dysregulation of IL-11 expression by the mesangial cells? Which has nothing to do with the Th1/Th2 paradigm.

Kimpen: There is a lot to be said that the Th1/Th2 paradigm is not the immunological system explaining the serious changes in the airways during RSV bronchiolitis, nor the subsequent wheezing periods. As far as IL-11 is concerned, the only paper on IL-11 and RSV is a paper by Einarsson et al. [J. Clin. Immunol., 1996;97:915-921; Ed.], who just looked at the presence of IL-11 in the airways of children with bronchiolitis as well as the presence of IL-11 in supernatants of cells that were infected with RSV, but they did not examine the trigger mechanisms for this IL-11.

Dubois: I was intrigued by the G protein that induced Th2 responses in vitro. How important is that for the whole virus, particular the whole nonliving virus. Of course, living replicating virus will usually elicit pretty good Th1 responses and that does not seem to be the case here. What is the overall net contribution of that particular protein to skewing things to Th2?

Kimpen: There is still no vaccine, because the whole virus is unpredictable in the way it induces all kinds of cytokines. One has to define the proteins that are important for protection and use them in subunit vaccines, and not include those proteins that are immunopathogenic. The F protein, for example, seems to be a protective protein, but the whole G protein is immunopathogenic. However, if you take one piece out of the G protein, and splice it together, it is immunogenic and not immunopathogenic.

Björkstén: It used to be said that maternal immunity was a major factor for the bronchiolitis and this was precisely the reason why the outcome was worse during the first 6 months of age. The maternal transplacental IgG antibody would actually create the inflammation and the disease was due to the defense mechanisms, with the inflammation due to the lack of a functional mucosal immunity in the baby. Then there was vaccination, a killed vaccine, and it turned out to be making things worse. There was an increase in RSV bronchiolitis and death. This was again ascribed to a systemic immunity in the lack of a mucosal immunity. Is that hypothesis dead now?

Kimpen: That hypothesis has been refuted. There are several arguments to prove that the immunopathology is not antibody related. We have seen a similar story with measles, in that the first vaccine was given and upon natural infection the children became sicker than the controls; that was an immune complex-mediated disease. This is not the case with RSV. The second is that the higher the antibody levels in small children, the more protected they seem to be against severe RSV bronchiolitis. If antibody from the mother would contribute to the disease, we would expect exactly the opposite.

De Jongste: There are so many respiratory viruses, and RSV occurs in almost all infants during the first 2 years of life, but there are many more, like adenovirus, capable of damaging the airways in a very pronounced way. There may be other viruses that also do some damage and may explain some of the lower airway symptoms during the first years of life.

Martinez: The problem I have with that hypothesis is that we don't see many of those cases. We see postadenovirus bronchiolitis obliterans in Tucson, but 95% of the children are Native American children, and it is very, very rare to see something like that in Caucasian or black children. My feeling is that the most common form of bronchial obstruction during the first years of life is caused by RSV and parainfluenza.

Kimpen: If you look at reviews it is said that 60-70% of all bronchiolitis cases are RSV bronchiolitis. I have to admit that if we see bronchiolitis, it is almost 100% RSV.

Martinez: It is quite likely that different viruses could be interacting either via the immune system or IL-11, or whatever.

Platts-Mills: The whole population gets RSV. Have you looked at the immune response in the whole population to say whether you can really distinguish the immune response of those children who are getting RSV and who don't end up in the ER?

Kimpen: All the data in the literature on RSV infections, almost all, 99%, are from patients who have been admitted to the hospital, which is something like 4% of the total population of children with RSV infections.

Platts-Mills: You are avoiding one of the conclusions about the vaccination studies. In the vaccination study, when the children did very badly, some of them had eosinophilic infiltrations in the lungs.

Kimpen: In one of the studies children that died after RSV vaccination demonstrated eosinophilic infiltration in the lung, and, in the other study, of the patients that got sicker from the vaccine, 11% had eosinophilia.

Platts-Mills: Apparently this phenomenon that occurred with RSV vaccination, where the children subsequently may have got a natural infection that was eosinophilic and dangerous, does not seem to appear with natural RSV infection.

Sterk: You have shown that the cytokine response is determined by the protein expression of the virus. As you know, Dr. Hegele from the Vancouver group has shown that RSV infection might persist weeks or months, at least in the guinea pig model [Eur. Respir. J. 1997;10:20-26; Ed.]. This raises the possibility that the cytokine response switches when an infection becomes persistent. Is there any evidence of the cytokine response after persistent infections being different from the acute response? In animals or in man?

Kimpen: There has not been a report on persistent RSV infection in the human. Usually the virus is gone after 7 days. We have always believed, and I still believe, that RSV is a purely mucosal infection, but there have been two papers, showing by PCR techniques, that at least in a subgroup of patients RSV can be present in peripheral blood mononuclear cells. If it is the rule, then the whole path of persistent infection opens up and we will have to pursue that. However, until now, there is no evidence for that.

Tiddens: We performed several bronchoscopies on children suffering from severe bronchiolitis who were treated with extracorporeal membrane oxygenation. We noticed that the sputum of these RSV-infected children was extremely thick and very difficult to evacuate from the airways by suction. We think that the thick sputum plays an important role in the sever airway obstruction in these children. Do you know what causes this hypersecretion of thick mucus in RSV-infected children?

Kimpen: If you are looking at airways of children with RSV bronchiolitis you see sloughing of the epithelium and mucous secretion. Is this due to the virus infection of the epithelial cells and the destruction by CD8-positive cells or is this due to one of the immunological mediators that is released upon RSV infection? Nobody knows.

Postma: In relation to the data you presented and the Martinez data: Is it still relevant to study RSV infections in relation to the development of asthma?

Kimpen: Yes, because there is an association between RSV infection and recurrent wheezing in early childhood. It is important to unravel the mechanisms involved. This will perhaps lead to the identification of a predisposed phenotype.

Platts-Mills: It would be very helpful to make a distinction between the recurrent wheezing that follows early viral infection and early episodes of asthma in an allergic child. This distinction could come out of research on RSV. I would go further. It is terribly important to understand this syndrome of what happens after RSV, because you cannot study any of it unless you separate out what is happening during these first 6 years, because during these first 6 years the atopics are appearing and other children who have RSV are having wheezy episodes. It is essential to separate these.

Martinez: I fear that I am in agreement with you. I think asthma is a progressive disease in a significant number of cases. RSV-associated wheezing in my opinion is not a progressive disease, it is a disease that goes away with time and maybe it comes back again when you have COPD, but it is not a progressive disease. In that case, the therapeutic approach has to be very different. But, as of today, when we see a 4-year old wheezer, or a 3-year old, we don't have a good way of distinguishing between these subjects, and if we had a good way, if we had some markers, genetic or others, that would allow us to distinguish between them, we could perhaps select those in whom we are going to start therapy of any type, in an attempt to prevent this progressive nature of asthma; I think this is a very important issue.

Kimpen: There might be one good way to distinguish them, and that is their response to treatment. A 2- or 3-year-old with virus-induced wheezing episodes is very hard to treat with bronchodilators or with corticosteroids.

Aalberse: I want to go back to immunology and discuss viruses as adjuvant factors. Most people would believe that bacterial products are negative adjuvant factors for IgE production, but are in doubt about viruses. Is there any evidence that viruses are either positive or negative adjuvant factors in human atopic sensitization?

Kimpen: The evidence is controversial. If you look at RSV again, there is no evidence that atopics get more severe disease due to RSV. Epidemiologically, one does not observe in the groups with RSV bronchiolitis a higher proportion of subjects with an atopic history. On the other hand, when you are infecting animals with RSV, you can more easily sensitize them to, for example, ovalbumin. Three is also an epidemiological human study showing that during RSV bronchiolitis you may get sensitized to aeroallergens. So, the data about viruses and sensitization are conflicting.

Aalberse: What about viruses in the gut, enteric viruses, hepatitis, etc. Do you accept that that might influence sensitization to aeroallergens?

Kimpen: Again, there is no data on that. The most prominent viral gastrointestinal infection is rotavirus. People have not looked at rotavirus and sensitization.

Vercelli: Viruses can induce a protein kinase (PKR). This can dimerize with STAT-1 to activate STAT-1-regulated genes, which suggests a role in isotype switching and IFN--dependent regulation. This would suggest that viruses at least could alter immune responses.

Platts-Mills: We lack any epidemiology that suggests that RSV infection is actually increasing sensitization.

Holt: I agree with you, but let's go back to what Dr. Aalberse was asking, which is really a theoretical question. At least in the animal system we now know that viral infections, like parainfluenza, for example, cause enormous changes in the airway dendritic cell populations; they recruit them in huge amounts. There are reasons to believe that they may influence bystander immune responses to inhalant allergens, but so far as data is concerned in the human, it is not really known. We have done one pilot study that only looked at about 40 children (20 that did or did not get RSV infection) from age 3 months to age 9 months, and looked at Fel d 1 and house dust mite responses before, during, and after the RSV season. So, quite often the key observation points were 2 to 3 weeks after infection. We could not really find any evidence for upregulation of the Th2 responses in that cohort. But what we did see, and we don't really know what the significance is, was a quite substantial increase in background levels of IFN- production. So, it may well be that this is one example of how a good, strong virus infection might be able to start upregulating adaptive immune function.

	Footnotes

Correspondence and requests for reprints should be addressed to J. L. L. Kimpen, M.D., Wilhelmina Children's Hospital, University Medical Center Utrecht, P.O. Box 85090, 3508AB Utrecht, The Netherlands. E-mail: j.kimpen{at}wkz.azu.nl

	References

TOP INTRODUCTION WHEEZING-ASSOCIATED RESPIRATORY... ACUTE VIRUS-INDUCED ASTHMA... POSTBRONCHIOLITIS WHEEZING VIRAL INFECTIONS PREDISPOSING... CONCLUSION DISCUSSION REFERENCES

1. Martinez, F. D., A. L. Wright, L. M. Taussig, C. J. Holberg, W. Halonen, W. J. Morgan, and the Group Health Medical Associates. 1995. Asthma and wheezing in the first six years of life. N. Engl. J. Med. 332: 133-138 [Abstract/Free Full Text].

2. Monto, A. S.. 1995. Epidemiology of respiratory viruses in persons with and without asthma and COPD. Am. J. Respir. Crit. Care Med. 151: 1653-1658 [Abstract].

3. Seear, M., and D. Wensley. 1997. Chronic cough and wheeze in children: do they all have asthma? Eur. Respir. J. 10: 342-345 [Abstract].

4. Hoo, A.-H., M. Hensschen, C. Dezateux, K. Costeloe, and J. Stocks. 1998. Respiratory function among preterm infants whose mothers smoked during pregnancy. Am. J. Respir. Crit. Care Med. 158: 700-705 [Abstract/Free Full Text].

5. Johnston, S. L., P. K. Pattemore, G. Sanderson, S. Smith, F. Lampe, J. Josephs, P. Symington, S. O'Toole, S. H. Myint, D. H. Tyrrell, and S. T. Holgate. 1995. Community study of the role of viral infections in exacerbations of asthma in 9-11-year-old children. Br. Med. J. 310: 1225-1229 [Abstract/Free Full Text].

6. Noah, T. L., and S. Becker. 1993. Respiratory syncytial virus-induced cytokine production by a human bronchial epithelial cell line. Am. J. Physiol. 265: L472-L478 [Abstract/Free Full Text].

7. Olszewska-Pazdrak, B., A. Casola, T. Saito, R. Alam, S. E. Crowe, F. Mei, P. L. Ogra, and R. P. Garofalo. 1998. Cell-specific expression of RANTES, MCP-1, and MIP-1 by lower airway epithelial cells and eosinophils infected with respiratory syncytial virus. J. Virol. 72: 4756-4764 [Abstract/Free Full Text].

8. Einarsson, O., G. P. Geba, Z. Zhu, M. Landry, and J. A. Elias. 1996. Interleukin-11: stimulation in vivo and in vitro by respiratory viruses and induction of airways hyperresponsiveness. J. Clin. Invest. 97: 915-924 [Medline].

9. Grünberg, K., H. H. Smits, M. C. Timmers, E. P. A. de Klerk, R. J. E. M. Dolhain, E. C. Dick, P. S. Hiemstra, and P. J. Sterk. 1997. Experimental rhinovirus 16 infection: effects on cell differentials and soluble markers in sputum in asthmatic subjects. Am. J. Respir. Crit. Care Med. 156: 609-616 [Abstract/Free Full Text].

10. Jamaluddin, M., R. Garofalo, P. L. Ogra, and A. R. Brasier. 1996. Inducible translational regulation of the NF-IL-6 transcription factor by respiratory syncytial virus infection in pulmonary epithelial cells. J. Virol. 70: 1554-1563 [Abstract].

11. Garofalo, R., M. Sabry, M. Jamaluddin, R. K. Yu, A. Casola, P. L. Ogra, and A. R. Brasier. 1996. Transcriptional activation of the interleukin-8 gene by respiratory syncytial virus infection in alveolar epithelial cells: nuclear translocation of the RelA transcription factor as a mechanism producing airway mucosal inflammation. J. Virol. 70: 8773-8781 [Abstract].

12. Spender, L. C., T. Hussell, and P. J. M. Openshaw. 1998. Abundant IFN- production by local T cells in respiratory syncytial virus-induced eosinophilic lung disease. J. Gen. Virol. 79: 1751-1758 [Abstract].

13. McConnochie, K. M., and K. J. Roghman. 1984. Bronchiolitis as a possible cause of wheezing in childhood: new evidence. Pediatrics 74: 1-10 [Abstract/Free Full Text].

14. Korppi, M., L. Kuikka, T. Reijonen, K. Remes, K. Juntunen-Backman, and K. Launiala. 1994. Bronchial asthma and hyperreactivity after early childhood bronchiolitis or pneumonia. Arch. Peditr. Adolesc. Med. 148: 1079-1084 .

15. Pullan, C. R., and E. N. Hey. 1982. Wheezing, asthma, and pulmonary dysfunction 10 years after infection with respiratory syncytial virus in infancy. Br. Med. J. 284: 1665-1669 .

16. Bont, L., C. J. Heijnen, A. Kavelaars, W. M. van Aalderen, F. Brus, J. T. Draaisma, S. M. Geelen, H. J. van Vught, and J. L. Kimpen. 1999. Peripheral blood cytokine responses and disease severity in respiratory synctial virus bronchiolitis. Eur. Respir. J. 14: 144-149 [Abstract].

17. Openshaw, P. J. M., and D. R. O'Donnell. 1994. Asthma and the common cold: can viruses imitate worms? Thorax 49: 101-103 [Free Full Text].

18. Sandford, A., T. Weir, and P. Paré. 1996. The genetics of asthma. Am. J. Respir. Crit. Care Med. 153: 1749-1765 [Abstract].

19. Kneyber, M. C. J., A. H. Brandenburg, Ph. T. Rothbarth, R. de Groot, A. Ott, and H. A. van Steensel-Moll. 1996. Relationship between clinical severity of respiratory syncytial virus infection and subtype. Arch. Dis. Child. 75: 137-140 [Abstract/Free Full Text].

20. Román, M., W. J. Calhoun, K. L. Hinton, L. F. Avendaño, V. Simon, A. M. Escobar, A. Gaggero, and P. V. Díaz. 1997. Respiratory syncytial virus infection in infants is associated with predominant Th2-like response. Am. J. Respir. Crit. Care Med. 156: 190-195 [Abstract/Free Full Text].

21. Alwan, W. H., F. M. Record, and P. J. M. Openshaw. 1993. Phenotypic and functional characterization of T cell lines specific for individual respiratory syncytial virus proteins. J. Immunol. 150: 5211-5218 [Abstract].

22. Tang, Y.-W., and B. S. Graham. 1997. T cell source of type 1 cytokines determines illness patterns in respiratory syncytial virus-infected mice. J. Clin. Invest. 99: 2183-2191 [Medline].

23. Srikiatkhachorn, A., and T. J. Brachiale. 1997. Virus-specific memory and effector T lymphocytes exhibit different cytokine responses to antigens during experimental murine respiratory syncytial virus infection. J. Virol. 71: 678-685 [Abstract].

24. Martinez, F. D., D. A. Stern, A. L. Wright, L. M. Taussig, M. Halonen, and Group Health Medical Associates. 1995. Association of non-wheezing lower respiratory tract illnesses in early life with persistently diminished serum IgE levels. Thorax 50: 1067-1072 [Abstract/Free Full Text].

25. Von Mutius, E., F. D. Martinez, and C. Fritzsch. 1994. Skin test reactivity and number of siblings. Br. Med. J. 308: 692-695 [Abstract/Free Full Text].

26. Von Mutius, E., F. D. Martinez, and C. Fritzsch. 1994. Prevalence of asthma and atopy in two areas of West and East Germany. Am. J. Respir. Crit. Care Med. 149: 358-364 [Abstract].

27. Shirakawa, T., T. Enomoto, S. Shimazu, and J. M. Hopkin. 1997. The inverse association between tuberculin responses and atopic disorder. Science 275: 77-79 [Abstract/Free Full Text].

28. Schwarze, J., E. Hamelmann, K. L. Bradley, K. Takeda, and E. W. Gelfand. 1997. Respiratory syncytial virus infection results in airway hyperresponsiveness and enhanced airway sensitization to allergen. J. Clin. Invest. 100: 226-233 [Medline].

29. Sigurs, N., R. Bjarnason, F. Sigurbergsson, B. Kjellman, and B. Björkstén. 1995. Asthma and immunoglobulin E antibodies after respiratory syncytial virus bronchiolitis: a prospective cohort study with matched controls. Pediatrics 95: 500-505 [Abstract/Free Full Text].